Acute Myeloid Leukemia (AML) is the most lethal hematological malignancy and is the cause of more than 10,000 deaths in the US annually. AML is typically treated by chemotherapy, though patients often relapse and have limited therapeutic options. The promyelocytic subtype of AML is successfully treated by differentiation therapy - use of all-trans-retinoic acid (ATRA) to induce cellular differentiation and loss of proliferation in leukemic blasts. Other AML subtypes, however, show minimal ATRA responsiveness. Recent work has suggested that this block to non-APL AML differentiation is epigenetic in nature. Stable - yet reversible - chromatin alterations are thought to render these AML cells unable to activate myeloid differentiation gene expression programs. This project aims to use RNAi screening technology to identify histone-modifying enzymes responsible for keeping AML cells in their undifferentiated state. The main focus of the proposed research will be to determine whether inhibition of candidate enzymes induces myeloid differentiation in AML cell tissue culture models and reduces disease burden in mouse AML models. A secondary focus will be to understand how, on a molecular and biochemical level, the identified enzymes are functioning to oppose myeloid differentiation. Successful identification and molecular understanding of such enzymes would directly suggest their candidacy as potential therapeutic targets for non-APL AML.